PROJECT SUMMARY/ABSTRACT Olfactory deficits are a core feature and pre-clinical sign of numerous brain diseases, including schizophrenia. The olfactory system provides direct access to orbitofrontal-limbic neurocircuitry implicated in the disease con- ditions and holds a unique promise for understanding aberrant neurodevelopment processes. However, a major hurdle for studies of olfaction is the lack of non-invasive methods to capture the underlying neurophysiological substrates of olfactory loss. To date, clinical evaluation of olfaction has been limited to psychophysical as- sessment, which is subjective and uninformative regarding the underlying abnormalities. In the brain, small ar- terioles with diameters up to 100-150 microns are the primary regulator of local tissue perfusion. Lymphatic vessels have also been identified in the brain, which are believed to play a crucial role in the clearance of waste products. Quantitative measurement of the small blood and lymphatic vessels in the olfactory system would provide biologically meaningful information on olfactory loss, and would significantly enhance efforts for the prediction and staging of brain diseases. Here, we propose to develop and optimize MRI techniques for the quantitative measurement of small blood and lymphatic vessels in the human olfactory cortex with the following aims: Aim 1: To develop and optimize MRI methods for measuring blood volume in arteriolar and venous mi- crovessels separately in the olfactory cortex. The olfactory cortex is notoriously difficult for MRI due to the well-known signal loss caused by the susceptibility effects at the boundary between tissue and nasal cavity. We will develop and optimize new MRI sequences for the olfactory regions to recover signal loss close to the nasal cavity. Aim 2: To develop and optimize MRI methods for measuring dynamic signal changes in small lymphatic vessels in the brain. Lymphatic vessels have recently been found in the dura mater and around the cribriform plate in the olfactory area in the brain. Non-invasive imaging methods for the cerebral lymphatic vessels are extremely scarce and are mostly limited to large lymphatic ducts only. In addition, the existing methods cannot detect dynamic lymphatic signal changes with sufficient temporal resolution due the long scan time needed. Based on previous work, we propose to use contrast agent-based MRI methods to measure dynamic signal changes in small lymphatic vessels in the brain, from which vessel volume information can be deduced. Aim 3: To characterize small blood and lymphatic vessel abnormalities of the olfactory system in schizophrenia patients, and their association with the olfactory deficits assessed by behavioral tests. Taken together, the proposed studies will advance our understanding of the underlying physiological changes associated with olfactory deficits in schizophrenia, which may facilitate the development of disease biomarkers and potential treatment targets. Furthermore, the research will provide MRI methodologies that can be used to probe similar physiological changes in other brain regions and diseases.